Method of preparation of cyclopentanophenanthrene derivatives



United States Patent C) METHOD OF PREPARATION OF CYCLOPENTANO- PHENANTHRENE DERIVATIVES George Rosenkranz, Mexico City, Mexico, and Carl;

Djerassi, Birmingham, Mich., assignors, by mesne assignments, to Syntex S. A., Mexico City, Mexico, a corporation of Mexico No Drawing. Application February 17, I953;

1i Serial No. 337,432

Claims priority, application Mexico February 19, 1952 8 Claims. (Cl. 260-23955) 's'apogenin side chain may be readily degraded to the side chain characterizing compounds of the p'regnane series which may thereafter be converted to the various side chains characterizing the hormones. Considerabled ifficulty, however, has been found in producing cortical hormones which are oxygenated in ring C from diosgenin and an ideal starting material would be a sapogenin which c-ontai-ned such an oxygen function at position 11 of the molecule as well as the functional groups present in the molecule of diosgenin-- Sapogenins of this type, however, are heretofore unknown.

In accordance with the present invention, therefore, there has been discovered a novel method for producing hydroxy derivatives having a sapogenin side chain and the ring A structure characteristic of diosgenin. It has further been discovered in accordance with the present invention that these novel compounds may be prepared from 22-isoallospirostan-3B,1la-diol diacetate disclosed'in' United States patent application Serial Number 291,555.

The novel final compounds of the present invention, as for example A -22isospirosten-3fl,1la-diol and/or esters thereof are important intermediates for the production of cortical hormones having ll-oxy substituents. For example, A -22-isospirosten-3fi,1la-diol diacetate may be oxidati-vely degraded by known methods utilized for the degradation. of" the sapogenin sidechain to A -pregnadien'-3fi',lla-diol-20-one diacetate. The 16.-d-ouble bond may then be selectively saturated by hydrogenation in the presence of a palladium catalyst and the A -diester saponified to the free, diol. Dibromination of the resultant. A -pregnen-3m11a-diol-20-one followed by treatment with sodium iodide, followed by treatment with sodium acetate produces A -pregnen-3B,l1a,2l-triol-2O- one 21 monora'ce ta'te. Openauer oxidation of this last compound produces, M-pregnen-l la,2l-diol-3,20-di-one, 21 acetate. Oxidation with chromic. acid of the lla-hydroxy group then produces the known compound ILdehydro corticoster'on-e acetate.

The process of the present invention may be exemplified by the following equation:

Partial Saponification Followed by Oxidation Dehalogenatlon or Deiodination e tr In the above equation R represents an acyl group, i. e. the residue of any organic acid customarily utilized for the csterification of steroid alcohols, preferably R represents the residue of the lower fatty acid such as acetic or propionic or the residue of an aromatic acid such as benzoic. In the above equation, further, R represents the same acid residues as hereinbefore set forth and in addition may represent hydrogen. Ac represents the acetyl radical.

In practicing the process above outlined a suitable diester, as for example the diacetate of 22-isoallospirostan- 3B-l1a-diol, is treated with approximately one molar equivalent of a mild saponifying agent, as for example an alkali metal bicarbonate, to prepare the corresponding ll-mono ester, as for example the ll-mono acetate. This ll-mono acetate can then be oxidized, as for example with chromic acid N-bromacetamide or with an aluminum alkoxide in the presence of a hydrogen acceptor, to produce the corresponding ll-mono ester of 22-isoallospirostan-11a-ol-3-one.

Before proceeding with the next step of the process, i. e. the polybromination, the mono ester may be saponified to produce the free 22-isoallospirostan-llwol-B-one. For the polybromination, the free compound or the ester is treated with bromine in acetic acid in the presence of a few drops of hydrobromic acid. The 2,4,23-tribromo-22-isoallospirostan-l1a-ol-3-one ester or free compound which is thus obtained can then be treated with sodium iodide in a ketone solvent in order to prepare the corresponding 2-iodo-23-bromo-M-ZZ-isospirosten- 11u-O1-3-0ne ester or the corresponding free compound. The 2-iodo-A compound thus produced can then either be completely dehalogenated or deiodinated. For the dehalogenation, a suitable agent is zinc in alcohol solution and the resultant compound is, for example A -22-isospirosten-lla-ol-ii-one acetate. In this particular case the X represents hydrogen.

In the alternative, instead of complete dehalogenation the 2-iodo-23-bromo-N-ZZ-isospirosten-1la-ol-3-one acetate may be deiodinated. For this purpose, reducing agents such. as chromous chloride, collidine, dimcthylaniline or sodium bisulfite may be utilized. Other tertiary amines may also be used. The 23-bromo derivative thus produced may then be debrominated by treatment with zinc or it may be utilized as such for the next step of the present process. In the case where the compound is merely deiodinated X as shown in the above equation represents bromine.

The A -22-isospirosten-l1a-ol-3-one, or its ll-ester, or its 23-bromo derivative can then be treated with a suitable acetylating agent such as isopropenyl acetate or acetic anhydride in the presence of an acid catalyst to form the corresponding enol acetate. Finally, the enol acetate can be treated with sodium borohydride to produce the desired A -22-isospirosten-3fi,1la-diol, which is preferably esterificd in situ to produce the corresponding 3,11 diester. Where the 23-bromo derivative is utilized, as will be understood, the corresponding 23-bromo-A -22- isospirosten-33,1la-diol and/or its ester is prepared. The 23-bromo derivative can then be dehalogenated by reduction with zinc as indicated in the following equation:

Br w I Dehalogenation amnesia tives are described in'the present specification, it will be understood that Where the C-22 normal sapogenins are referred to that an additional mol of bromine is present at C-2 3 The following specific examples serve to illustrate but are not intended to limit the present invention:

Example I An alcoholic solution of 2'2-isoallospirostan 3fi,11a diol dia'cetat'e' was refluxedfor 30' minutes with an aqueous solution of 111 molar equivalents of sodium bicarbonate (potassium bicarbonate can also be used). The mixture was poured into water and the precipitate was collected, washed to neutral, dried in'air and recrystallized from methanol to yield 22-isoallospirostan-3'fi,1la-diol 1 1 -m'onoacetat'e;

Example II' A solution of 1 g. of 22-isoa1lospiiostan-Bp,lla-diol l'l-m'onoace'tate in 30 cc. of glacial acetic'acid maintained at 15 C., was treated with a solution of 200 mg. of chromic acid in 2 cc. of water and cc. of acetic acid, which was added dropwise. The solution was stirred during 2 hours at room temperature and then poured into water. The precipitate was filtered and washed, and after recrystallization from ethyl acetate' it yielded 22- isoallos'pirostan-l1a-ol-3 one acetate.

Saponification of the acetate by refluxing with 5% methanolic potassium hydroxide yielded the free alcohol, namely 22-isoallospi'rostanl la-ol-3-one.

Example III 1 g. of 22-is oallospirostan-35,1la-diol ll-monoacetate was dissolved in a mixture of 140 cc. of toluene and of cyclo'h'exanone and 40 cc. of the mixture were distilled in order to remove traces of moisture. To the Boiling" solution it was added a solution of 1.20 g. of aluminum isopropylate in 50 cc. of anhydrous toluene in: the course of 45 minutes, maintaining a slow distillation during all this time. cc. of a concentrated solution of sodium-potassium tartrate were added to the cooled solution and the mixture was subjected to steam distillation for removal of the volatile components. The mixture was extracted with ether and the ether solution was washed with water, dried over sodium sulfate and evaporated to dryness. Recrystallization of the residue from ethyl acetate yielded 22-isoallospirostan-1la-ol-B- one acetate, identical to the one obtained according to Example II.

Example IV 440 mg. of N-brornoa-cetamide were added in small portions to a solution of 1 g. of 22-isoallospirostan-3/3,1ladiol ll-monoacetate in 25 cc. of pyridine maintaining the temperature at 20 during the operation. After standing overnight at room temperature, the solution was diluted with Water and extracted with ether. The ether layer was repeatedly washed with dilute hydrochloric acid and then with sodium bicarbonate and water, dried over sodium sulfate and evaporated to dryness. The residue crystallized from ethyl acetate to yield 22-isoallospirostan- 11a-ol-3-one acetate, identical to the one obtained according to Example V.

Example V A solution of 5.6 g. of 22-isoallospirostan-11a-ol-3-one acetate in 170 cc. of glacial acetic acid was mixed with 8 drops of a 4-normal solution of hydrobromic acid in acetic acid and the mixture was treated with a solution of 7.4 g. of bromine in 75 cc. of acetic acid which was added dropwise under continuous stirring and maintaining the temperature of the solution at 22 C. After keeping the mixture overnight at room temperature in order to complete the rearrangement of the 2,2-dibromo into the more stable 2,4-dibrorno configuration, it was poured into water and the precipitate was filtered and A U washed with water. 2,4,23 'tribronio-22 isoallospirostan- 11-a-ol-3-one acetate was thus obtained.

Example VI A solution of 5.2 g; of 2 ,4,23-tril' rom-o'-22-isoaflospiro s'tan-1'1a-ol-3-one acetate, such as obtained according to the previous example, and 18 g. of sodium iodide iirS'Qb cc. of acetone was refluxed during 3 hours and then kept standing at room temperature during 72 hours; The. solution was diluted with ether and washed with water, sodiumthiosulfate solution, sodium bicarbonate and water, dried over sodium sulfate and evaporated to dryness. Z-iodo -.23' bromo A -22-isospirostem11aol 3 one acetate was thus obtained which showed an ultraviolet absorption maximum at 137 mu (log e 4.25 and was used without further purification for the next experiment.

Example VII A solution of 4.1 g. of 2 ido-23 bromo-A -22-isospirosten-1*l a-ol-3-one acetate in 1500 cc. of alcohol was reflux'ed with g. of zinc dust during 5 hours. The-solution was filtered and the residual. zinc was well washed with ether. The combined filtrates were washed with water, dried over sodium sulfate and evaporated to dryness. Crystallization of the residue from chloroform-methanol yielded A -22-isospirosten-1'la ol 3 one acetate with: an ultraviolet absorption maximum. at 238- mp. (log. 64.28).

Sap'onification of the above acetate with 5% methanoli'c potassiumhydroxide (sodium hydroxide can be used instead) refluxing the solution during one hour under an atmosphere of nitrogen afforded the free A -22-isospi'rosten-l' la-ol-3'-one.

Example" VIII A solution of 3.2 g. of 2-ido23-bromo-A -22-isospirostair-'1 la ol-3-one acetate in 350cc. of acetone and 1.00 cc. of dioxane was mixed, under an atmosphere of carbon dioxide, with a solution of chromous chloride prepared from 25 g. of chomic chloride, according to the method described by Rosenkranz, Mancera, Gatica and Djerassi, J. Chem. 800., 72,4077 (I950). After 15 minutes, the solution was poured into water, extracted with ether, washed with sodium bicarbonate and water, dried and concentrated to a small volume until crystallization started. The precipitate was filtered, yielding 23-bromo- A -isospirosten-11a-ol-3-one acetate with an ultraviolet absorption maximum at 238 my, (log 5 4.28).

Example IX A solution of 2 g. of 23bi-omo-A -22-is'ospirosten- 1 1a-ol-'3'-one acetatein .60 cc. of alcohol was refluxed during 2 hours with 7g. of zinc dust, and the mixture was then worked up as described in Example VII. Recrystallization from chloroform-methanol aiiorded A 22-isospirosten-11a-ol-3-one acetate, identical to the one described in Example VII.

Example X A solution of 1g. of A -22-isospirosten-l1a-ol-3-one acetate in 60 cc. of benzene was treated with mg. of p-toluenesulfonic acid and 4 cc. of isopropenyl acetate (the free A -22-isospirosten-1la-ol-3-one can be used instead of the acetate, yielding the same result). The solution was slowly concentrated in the course of 5 hours to a final volume of 15 cc.; 4 cc. more of isopropenyl acetate were added at the end of the first hour and 2 cc. more at the end of the second and third hours. The mixture was concentrated to dryness under vacuum, diluted with ether and washed with water, sodium bicarbonate and Water, dried and evaporated to dryness. The residue crystallized from a mixture of ether and acetone to which one drop of pyridine had been added. A -22- isospirostadien-3,1la-diol diacetate was thus obtained, with an ultraviolet absorption maximum at 235 my. (log a 4.05). The infrared spectrum, determined in chloroform solution, showed a maximum at 1736 cm.*-

(acetate) and showed no band of a,B-unsaturated keto groups.

The same reaction carried out on the corresponding 23-bromo derivative gave in this case 23-bromo-A 22- isospirostadien-3-11u-diol diacetate with the same physical characteristics as the enol acetate described above.

Example X1 A -22-isospirostadien-3,1la-diol diacetate was also obtained by refluxing A -22-isospirosten-11a-ol-3-one with acetic anhydride in the presence of p-toluenesulfonic acid and concentrating the solution in the course of 5 hours to one fifth of its original volume and then following the procedure described in Example X.

Example XII l g. of A -22-isospirostadien3,1la-diol diacetate was dissolved in 40 cc. of dioxane and 60 cc. of methanol. The solution was cooled in ice and treated with a solution of 1.6 g. of sodium borohydride in 40 cc. of methanol and 3 cc. of water, which was added in one portion. The mixture was kept overnight at a temperature of C. and then heated during 30 minutes at the temperature of the steam bath. It was diluted with water and extracted with chloroform, washed, dried over sodium sulfate and evaporated to dryness. The residue was directly acetylated with pyridine and acetic anhydride to give A -22-isospirosten-3B,llu-diol diacetate. This substance showed no selective absorption in the ultraviolet spectrum and in the infrared it had a band at 1736 cmr typical of acetates, and had no band of free hydroxy groups.

Saponification of this compound by refluxing with 5% methanolic sodium (or potassium) hydroxide gave the free A -22-isospirosten-3fi,1la-diol.

The same reaction carried out with the corresponding 23-bromo derivative gave in this case the corresponding 23-bromo-A -22-isospirosten-3 13,1 la-diol.

Example XIII A solution of 4 g. of 23-bromo-A -22-isospirosten- 3 3,11a-di01 diacetate in 120 cc. of alcohol was refluxed during 8 hours with 12 g. of zinc dust. The solution was filtered and evaporated to dryness. The residue crystallized from acetonehexane to give A -22-isospirosten-3B,11u-diol diacetate identical to the compound obtained according to Example XII.

We claim:

1. A process for the production of a A -spirosten-3fl, lla-diol which comprises treating an allospirostan-Bfi, lloz-diOl diacetate with approximately one molar equivalent of a mild saponifying agent to produce the corre- Cit sponding ll-mono acetate, treating the ,ll-mono acetate with an oxidizing agent to produce an allospirostan-llaol3-one acetate polybrominating the allospirostan-llaol-3-one acetate to produce the corresponding 2,4,23-po1ybrornoallospirostan-l1u-ol-3one acetate, treating the polybromo compound with sodium iodide to produce the corresponding 2-iodo-23-bromo-A -spirostan-1 111-01-3-0116 acetate, treating said last mentioned compound with zinc to dehalogenate and form a A -spirosten-11a-ol-3-one acetate, treating said last mentioned acetate with an acetylating agent in the presence of an acid catalyst to produce the corresponding A -spirostadien-3,1la-diol diacetate and finally reducing said last mentioned diacetate with sodium borohydride.

2. A process for the production of a A -spirosten-3fi, llec-dlOl which comprises, treating an allospirostan-3B, lla-diOl diacetate with approximately one molar equivalent of a mild saponifying agent to produce the corresponding ll-mono acetate, treating the ll-mono acetate with an oxidizing agent to produce an allospirostan-llaol-3-one acetate polybrominating the allospirostan-llaol-3-one acetate to produce the corresponding 2,4,23- polybromoallospirostamlla-ol-B-one acetate, treating the polybromo compound with sodium iodide to produce the corresponding 2-iodo-23-bromo-A -spirostan-l la-ol-3-one acetate, treating the 2-iodo-23-bromo-compound with a mild reducing agent to deiodineate said compound and form a 23-bromo- -spirosten-11-ol-3-one acetate, treating said last mentioned 23 bromo compound with an acetylating agent in the presence of an acid catalyst to produce the corresponding 23-bromo-A -spirostadien-3, lla-diol-diacetate reducing said last mentioned 23-bromo compound with sodium borohydride to produce the corresponding 23-bromo-A -spirosten-3B,1lu-diol and finally treating said last mentioned compound with zinc to remove the 23-bromo group.

3. The process of claim 1 wherein the compounds are members of the 22-iso series.

4. The process of claim 2 wherein the compounds are members of the 22-is0 series.

5. A compound selected from the group consisting of A -spirosten-3fi,1la-diol, lower fatty acid esters and benzoic acid esters thereof.

6. A -22-isospirosten-3fl, lla-diol.

7. A -22-isospirosten-3fi, llm-diol diacetate.

8. A process for the production of A -22-isospirosten- 3B, llcc-CliOl diacetate which comprises treating A -ZZ- isospirostadien-3, llnc-diOl diacetate with sodium borohydride followed by acetylation.

No references cited. 

5. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF $5-SIROSTEN-3B,11A-DIOL, LOWER FATTY ACID ESTERS AND BENZOIC ACID ESTERS THEREOF. 